A Homozygous Frameshift Variant in KHDC4 Is Associated With a Syndromic Inherited Retinal Disease in Humans

Inherited retinal diseases (IRDs) are genetically heterogeneous and often remain unsolved despite advanced sequencing. This study investigated two siblings from a consanguineous Arab-Christian family presenting with a syndromic IRD. Exome sequencing revealed a homozygous frameshift variant (c.1535_1538del:(p.Lys512Argfs*8) in the KHDC4 gene, which segregated with disease in an autosomal recessive pattern. In vitro overexpression of the mutant protein showed aberrant sub-cellular localization, and an in vivo zebrafish knockout model exhibited mild retinal dysfunction. These findings establish KHDC4 as a novel candidate gene for syndromic IRDs in humans, expanding the genetic landscape of the IRDs.